The efficacy of radiation and chemical methods in the treatment of cancers has been limited by a lack of selective targeting of tumor cells by the therapeutic agent. In an effort to spare normal tissue, current tumor treatment methods have therefore restricted radiation and/or chemical treatment doses to levels that are well below optimal or clinically adequate. Thus, designing compounds that are capable, either alone or as part of a therapeutic method, of selectively targeting and destroying tumor cells, is a field of intense study.
Because of the known affinity of porphyrins to neoplastic tissues, there has been intense interest in using porphyrins as delivery agents in the treatment of neoplasms in brain, head and neck, and related tumors. Porphyrins in general belong to a class of colored, aromatic tetrapyrrole compounds, some of which are found naturally in plants and animals, e.g., chlorophyll and heme, respectively.
Porphyrins and other tetrapyrroles with relatively long singlet lifetimes have already been used to treat malignant tumors using photodynamic therapy (PDT). In PDT, the patient is first injected with a photosensitizing drug, typically a porphyrin. The tumor cells, now photosensitized, are susceptible to destruction when exposed to an intense beam of laser red light. The biochemical mechanism of cell damage in PDT is believed to be mediated largely by singlet oxygen, which is produced by transfer of energy from the light-excited porphyrin molecule to an oxygen molecule. However, PDT has been limited predominantly by the photosensitizing compounds, which have lower than adequate selectivity to tumor cells and higher than optimal toxicity to normal tissue.
A promising new form of cancer therapy is boron neutron-capture therapy (BNCT). BNCT is a bimodal cancer treatment based on the selective accumulation of a stable nuclide of boron, boron-10, or 10B, in the tumor, followed by irradiation of the tumor with thermalized neutrons. The thermalized neutrons impinge on the boron-10, causing nuclear fission (decay reaction). The nuclear fission reaction causes the highly localized release of vast amounts of energy in the form of high linear-energy-transfer (LET) radiation, which can kill cells more efficiently (higher relative biological effect) than low LET radiation, such as x-rays.
Boron-10 undergoes the following nuclear reaction when captured by a thermal neutron:
                                         10                ⁢        B            +      n        →                           11            ⁢      B                                   11            ⁢      B        →                                       7                ⁢        Li            +                                   4                ⁢        He            +              γ        ⁡                  (                      478            ⁢                                                  ⁢            keV                    )                    In this nuclear reaction, a boron-10 nucleus captures a neutron forming the metastable nuclide 11B, which spontaneously and nearly instantaneously disintegrates into a 4He and 7Li particle, which together possess an average total kinetic energy of 2.34 MeV. These two ionized particles travel about 9 μm and 5 μm (7±2 μm) in opposite directions in soft tissue, respectively.
The distances traveled by the 4He and 7Li particles are comparable to the diameter of many tumor and tumor-associated cells. Therefore, the efficacy of BNCT resides in the production of highly localized, high LET ionizing radiation within the tumor. The targeted tumor thus receives a large dose of radiation while sparing surrounding normal tissue.
In the case of brain tumors, after administration of the boron compound, the patient's head is irradiated in the general area of the brain tumor with an incident beam or field of epithermal (0.5 eV-10 keV) neutrons. The neutrons become progressively thermalized (average energy approximately 0.04 eV) as they penetrate deeper into the head. As the neutrons become thermalized, they are more readily captured by the boron-10 concentrated in the tumor cells and/or tumor supporting tissues, since the capture cross section is inversely proportional to the neutron velocity.
In BNCT, the boron-containing compound must be non-toxic or of low toxicity when administered in therapeutically effective amounts, as well as being capable of selectively accumulating in cancerous tissue. Although p-boronophenylalanine (BPA) has the advantage of low chemical toxicity, it accumulates in critical normal tissues at levels that are less than desirable. In particular, ratios of boron concentration in tumors relative to normal brain and tumors relative to blood are approximately 3:1. Such low specificity limits the maximum dose of BPA to a tumor since the allowable dose to normal tissue is the limiting factor.
A particular class of synthetic porphyrins, known as tetraphenyl porphyrins, have garnered intense interest in the design of new boron carrier compounds for BNCT. Tetraphenylporphyrins (TPPs) contain four phenyl groups on the 5, 10, 15, and 20 positions of the porphyrin ring. An advantage of TPPs is their ease of synthesis.
The solubility of TPPs can be controlled by substituents, generally on the phenyl rings. Those TPPs containing sulfonate or carboxylate substituents are water-soluble. However, some of the carborane-containing TPPs have high lipophilic properties, which can require high amounts of non-aqueous excipients before administration into animals. High amounts of excipients may reduce the biological effect of the porphyrin by, for example, changing the microlocalization within the tumor cell such that the porphyrin may be bound to membranes instead of homogeneously distributed throughout the cell.
In addition, certain substituents such as amide, ester, or urea substituents are subject to hydrolysis. Such hydrolysis is particularly problematic when the substituents are employed to attach the carboranyl group to the porphyrin molecule, since hydrolysis results in loss of the carboranyl group before reaching the target.
Therefore, there continues to be an effort to reduce the lipophilic behavior of TPPs while not compromising their chemical stability. For example, international Patent Application No. WO 01/85736 by Vicente et al describes the synthesis and use of tetraphenylporphyrin compounds that contain hydrophilic carboranyl substituents. A salient feature of the Vicente compounds is the attachment of the carboranyl group to a phenyl ring exclusively by a carbon-carbon linkage. Though the carbon-carbon linkage is not prone to hydrolysis or other chemical attack, the substituent is significantly hydrophobic.
The choice of substituents on the phenyl rings of TPPs may also affect a compound's polarity and ability to target cellular membrane receptors. Various substituents are being studied for improved biodistribution of porphyrin compounds.
A porphyrin molecule has the advantage of having the ability to chelate metal ions in its interior. Such chelated porphyrins can additionally function as visualization tools for real-time monitoring of porphyrin concentration and/or diagnostic agents. For example, when chelated to paramagnetic metal ions, porphyrins may function as contrast agents in magnetic resonance imaging (MRI), and when chelated to radioactive metal ions, porphyrins may function as imaging agents for single photon emission computed tomography (SPECT) or positron emission tomography (PET).
There is a need for new compounds, especially boron-containing porphyrins, that have long retention times in tumors, and that selectively target and destroy tumor cells with minimal damage to normal tissue. In addition, there is a need for more effective methods for the treatment of brain, head and neck, and related tumors, and more particularly, more effective BNCT treatments and boron-delivery compounds used therein.